PVP REVIEW MEMO ADDENDUM FDA/CBER/OBE/DE/VSB
|Date:||February 19, 2010|
|SPONSOR:||Novartis Vaccines & Diagnostics, Inc|
|PRODUCT:||Menveo, Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine|
|FROM:||Michael Nguyen, MD
Medical Officer, Vaccine Safety Branch
|THROUGH:||Robert P. Wise, MD, MPH
Acting Director, Division of Epidemiology
|SUBJECT:||Addendum to the January 22, 2010 Pharmacovigilance Plan Review by David Martin|
The statistical reviewer, Barbara Krasnicka, noted in her review of study V59P13 that 8 events in the Menveo group appeared to be suicide attempts, while no such event was reported in the Menactra control group.
As described in the clinical review memo by Margaret Bash, January 28, 2010 (pages 18–19):
Study V59P13 was undertaken as a pivotal study to compare the safety and immunogenicity of MenACWY to the currently U.S licensed meningococcal conjugate vaccine Menactra.
Study V59P13 was a randomized, controlled, observer blind multicenter study conducted in the U.S. Subjects were administered either MenACWY or Menactra intramuscularly (IM) by anunblinded study vaccine administrator. The subjects were blinded to the study vaccine given. All safety follow-up performed by the investigator and study staff was also blinded. Blood was drawn before vaccination, at day 1, and after vaccination, at day 29 (window:+14 days). From day 29 to day 180 only safety was collected.
The secondary safety objective of V59P13 was:
To describe and compare the safety profile following a single injection of MenACWY (3 lots combined) to that following a single injection of Menactra administered to healthy adolescents or adults (11 to 55 years of age) defined as the percentage and number of subjects with: immediate hypersensitivity reactions (within 30 minutes) following vaccination; local and systemic reactions during the period study day 1 to 7; adverse events (AEs) reported during the period study day 1 to 29; medically significant AEs reported during the period study day 30 to 180; serious adverse events (SAEs) reported from study day 1 to 180.
In study V59P13, 23 of 2663 (0.9%) Menveo subjects and 5 of 876 (0.6%) of control subjects reported serious adverse events. Among Menveo recipients 5 (0.19%) experienced intentional drug overdoses or suicide attempts, for a total of 8 such events as 1 subject had multiple attempts. Although none of these events were reported in the comparison group, closer examination of the clinical narrative of an event coded as “therapeutic agent toxicity” indicates that this adolescent experienced an intentional overdose. If so, 1 (0.11%) of Menactra vaccinees experienced suicide attempts or intentional drug overdose. Thus, a similar proportion of subjects (0.19% vs. 0.11%) experienced these adverse events.
Of note, only 2 of these events occurred within 30 days after vaccination (on days 2 and 11), both of whom were adolescents vaccinated with Menveo.
Novartis provided important epidemiologic information to place these events into context:
Suicide rates and attempted suicides are distressingly frequent events among US adolescents. Mulye and colleagues recently published a comprehensive review of this topic, and reported that an annual suicide attempt rate among high school students of 6.9% (Mulye et al, J Adolescent Health, 2009). This rate was comparable to that in an earlier surveillance summary of youth risk behaviors compiled and issued by the Centers for Disease Control and Prevention (CDC). In contrast with Mulye’s analysis, which focused on existing published data sets and publications, the CDC used its own data capture system consisting of repeated cross sectional survey data of teens in grades 9-12 from 34 states. Despite these methodological differences between the two reports, the conclusions were remarkably concordant, with CDC reporting the rate of suicide attempts among adolescents of 8.8% per year (MMWR, surveillance summaries, 2002).
From these analyses, it is reasonable to accept that the rate of suicide attempts among adolescents ranges between 7-9% per year. In V59P13, of 3539 total subjects, 2180 enrolled subjects were adolescents between the ages of 11-19 years. Per protocol, each subject was to be followed for six months, and thus would contribute one half of a person-year each, leaving ~1090 person years of observation (for simplicity this ignores the small proportion of early drop outs). From that total, and taking the midpoint of the two estimates of suicide attempts between the two reports as 8% per year, in an “average” population, one would have expected approximately 87 suicide attempts to occur during the study period. In contrast, only 8 attempts were observed in this study, which yields a rate more than 10-fold below the US national average.
It is the opinion of the Division of Epidemiology that the reported events of suicide in the Menveo group do not rise to the level of a serious safety concern. Our review memo of the sponsor's pharmacovigilance plan supports this assessment. Moreover, the sponsor’s risk management plan includes a postmarketing commitment to assess safety among vaccine recipients aged 11–19 years that will include surveillance of suicidality, vaccine failure, neurologic and allergic reactions following vaccination.